Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric cancer. Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor α chain (IL-7Rα, encoded by IL7R), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, which genes cooperate with IL7R to drive leukemogenesis remain poorly defined. Here, we demonstrate that mutant IL7R alone is capable of inducing T-ALL with long-latency in stable transgenic zebrafish and transformation is associated with MYC transcriptional activation. Additionally, we find that mutant IL7R collaborates with Myc to induce early onset T-ALL in transgenic zebrafish, supporting a model where these pathways collaborate to drive leukemogenesis. T-ALLs co-expressing mutant IL7R and Myc activate STAT5 and AKT pathways, harbor reduced numbers of apoptotic cells and remake tumors in transplanted zebrafish faster than T-ALLs expressing Myc alone. Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential.

• Authors: Mariana L Oliveira, Alexandra Veloso, Elaine G Garcia, Sowmya Iyer, Clara Pereira, Vasco M Barreto, David M Langenau, João T Barata
• Journal: Leukemia (Leukemia) Vol. 36 Issue 6 Pg. 1533-1540 (06 2022) ISSN: 1476-5551 [Electronic] England
• PMID: 35581375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s).

Chemical References

• IL7R protein, human
• Interleukin-7 Receptor alpha Subunit
• Receptors, Interleukin-7

Topics

• Animals
• Animals, Genetically Modified
• Carcinogenesis (metabolism)
• Child
• Humans
• Interleukin-7 Receptor alpha Subunit (metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (pathology)
• Receptors, Interleukin-7 (genetics, metabolism)
• Signal Transduction (genetics)
• T-Lymphocytes (metabolism)
• Zebrafish (genetics, metabolism)